Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents:  2-Substituted-6-amino-5-phenylbicyclo[2.2.2]octanes

Javanmard, Sahar; Deutsch, Howard M.; Collard, David M.; Kuhar, Michael J.; Schweri, Margaret M.

doi:10.1021/jm990306k

Cited by 11 publications

(8 citation statements)

References 16 publications

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“…Cocaine analogs and chemical libraries of more than 300,000 compounds have been screened for differential activities in inhibiting cocaine analog binding and in blocking dopamine uptake (Chalon et al, 1999;Javanmard et al, 1999;Hoepping et al, 2000). Studies with these small molecules have identified the importance of many features of cocaine's structure for its ability to block dopamine uptake or to inhibit cocaine analog binding by DAT.…”

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confidence: 99%

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Lin

Uhl

2002

Mol Pharmacol

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Cocaine's blockade of dopamine reuptake by brain dopamine transporters (DAT) is a central feature of current understanding of cocaine reward and addiction. Empirical screening of smallmolecule chemical libraries has thus far failed to provide successful cocaine blockers that allow dopamine reuptake in the presence of cocaine and provide cocaine "antagonism". We have approached this problem by assessing expression, dopamine uptake, and cocaine analog affinities of 56 DAT mutants in residues located in or near transmembrane domains likely to play significant roles in cocaine recognition and dopamine uptake. A phenylalanine-to-alanine mutant in putative DAT transmembrane domain 3, F154A, retains normal dopamine uptake, lowers cocaine affinity 10-fold, and reduces cocaine stereospecificity. Such mutants provide windows into DAT structures that could serve as targets for selective cocaine blockers and document how combined strategies of mutagenesis and small molecule screening may improve our abilities to identify and design compounds with such selective properties.The dopamine transporter (DAT) is a putative 12-transmembrane domain (TM) protein that takes up dopamine into neurons of brain pathways that contribute to behavioral reward (Ranaldi et al., 1999;Redgrave et al., 1999). Cocaine blockade of dopamine uptake by the DAT expressed by these neurons has been identified as a crucial component for cocaine reward, suggesting that selective blockade of cocaine recognition in this pathway could have therapeutic importance for development of anticocaine medication Villemagne et al., 1999).To improve understanding of the ways in which DAT recognizes cocaine and dopamine, hundreds of cocaine analogs have been synthesized and hundreds of DAT mutant and chimeric molecules constructed and characterized (Kitayama et al

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confidence: 99%

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Lin

Uhl

2002

Mol Pharmacol

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“…Understanding the mechanism of the AChR and its inhibition is a longstanding and challenging problem (10) with major implications for medicine and drug addiction (11)(12). Two decades ago, single-channel current-recording (13) measurements led to the proposal of a simple and generally accepted mechanism in which inhibitors enter the open channel and block it (14-17) (the channel-blocking mechanism, Mechanism A in Fig.…”

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confidence: 99%

Mechanism-based discovery of ligands that counteract inhibition of the nicotinic acetylcholine receptor by cocaine and MK-801

Hess

Ulrich

Breitinger

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Nicotinic acetylcholine receptors (AChR) belong to a family of proteins that form ligand-gated transmembrane ion channels. They are involved in the fast transmission of signals between cells and the control of intercellular communication in the nervous system. A variety of therapeutic agents and abused drugs, including cocaine, inhibit the AChR and monoamine transporters and interfere with nervous system function. Here we describe a mechanism-based approach to prevent this inhibition. We had previously developed presteady-state kinetic (transient kinetic) techniques, with microsecond-to-millisecond time resolutions, for investigations of reactions on cell surfaces that allow one to determine the effects of inhibitors not only on the channel-opening probability but also on the opening and closing rates of the AChR channel. The transient kinetic measurements led to two predictions. T he nicotinic acetylcholine receptor (AChR) is the prototypical member of a family of structurally related membrane proteins, the ligand-gated ion channels (1). These proteins regulate intercellular communication between the approximately 10 12 cells of the mammalian nervous system, a process considered essential for brain function (2). Many therapeutic agents and abused drugs affect their function (3). For instance, the AChR is inhibited by the anticonvulsant MK-801 [(ϩ)Ϫdizocilpine] (4-6) and by several abused drugs, including cocaine (7-9). Cocaine affects more than three million people annually in the United States alone, at an estimated cost to society of more than 100 billion dollars.Understanding the mechanism of the AChR and its inhibition is a longstanding and challenging problem (10) with major implications for medicine and drug addiction (11-12). Two decades ago, single-channel current-recording (13) measurements led to the proposal of a simple and generally accepted mechanism in which inhibitors enter the open channel and block it (14-17) (the channel-blocking mechanism, Mechanism A in Fig. 1). Although several variations of this open-channelblocking mechanism have been proposed, including the conversion of an inhibitor-bound closed-channel conformation to a blocked open-channel form (18-21) (Mechanism B, Fig. 1), the open-channel-blocking mechanism, based mainly on singlechannel current or other steady-state kinetic measurements (14-21), has met the test of time during the last 20 years. In the techniques used for those measurements, the channel-activating ligand is in quasi equilibrium (steady state) with the receptor. The question we asked was: Can additional information about the receptor-mediated reactions be obtained by using presteadystate kinetic techniques? Recently, presteady-state kinetic techniques that are suitable for measuring receptor-mediated reactions on cell surfaces in the millisecond-to-microsecond time region were developed (22-31). The time resolution of the laser-pulse photolysis technique (23-26) is sufficient to investigate the reaction before the channel has opened. One can, therefore, obtain info...

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“…Pharmacology. The compounds were tested for their ability to inhibit the binding of [ 3 H]WIN 35,428 to the cocaine binding site on the DAT in synaptosomal membrane preparations from rat striatal tissue,7a [ 3 H]DA uptake into rat striatal synaptosomes, 7a, and [ 3 H]citalopram binding to the 5-HTT in synaptosomal membrane preparations from rat cortical tissue . The results are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

“…The work described here is part of an ongoing project aimed at the development of drugs that are targeted at the DAT to treat cocaine abuse. The goal is to synthesize agents that will fall along a continuum ranging from full agonist to full antagonist at the cocaine binding sites.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacology of Site Specific Cocaine Abuse Treatment Agents: 8-Substituted Isotropane (3-Azabicyclo[3.2.1]octane) Dopamine Uptake Inhibitors

2003

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A series of 8-substituted-3-azabicyclo[3.2.1]octanes (isotropanes) were synthesized and tested for inhibitor potency using [(3)H]WIN 35,428 binding at the dopamine (DA) transporter, [(3)H]citalopram binding at the serotonin (5-HT) transporter, and [(3)H]DA uptake assays. The synthesis started with a Mannich condensation of cyclopentanone, benzylamine, and fomaldehyde to afford N-benzyl-3-azabicyclo[3.2.1]octan-8-one (6). The 8-phenyl group was introduced by Grignard addition to ketone 6 or nucleophilic displacement via a triflate of the corresponding alcohol 7a. The 8beta-phenyl-8alpha-alcohols from Grignard addition generally have low affinity for the two transporters and do not effectively inhibit the uptake of [(3)H]DA. The 8beta-phenyl compound (14) without the hydroxyl group at C-8 was much more potent (22-fold) for [(3)H]WIN 35,428 binding inhibition than the corresponding 8beta-phenyl-8alpha-hydroxy compound (7a). The 8alpha-phenyl compound 8a was almost as potent as cocaine in binding to the DA transporter (IC(50) = 234 nM vs 159 nM for cocaine), whereas the C-8 epimer, compound 14, was somewhat less potent (IC(50) = 785 nM). The lower potency of 14 (beta-orientation of 8-phenyl group) as compared to 8a (alpha-orientation) was unexpected, based on modeling studies comparing the new compounds to WIN 35,065-2, an analogue of cocaine. The benzhydryl ethers at C-8 (17), analogous to the benztropines, had better selectivity than the corresponding phenyl compounds, 8a and 14, for the DA transporter as compared to the 5-HT transporter. The isotropane and benzisotropine analogues seem to bind in a manner that is more similar to that of the benztropine compounds 5 rather than those of cocaine and WIN 35,065-2.

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Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-Substituted-6-amino-5-phenylbicyclo[2.2.2]octanes

Cited by 11 publications

References 16 publications

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Dopamine Transporter Mutants with Cocaine Resistance and Normal Dopamine Uptake Provide Targets for Cocaine Antagonism

Mechanism-based discovery of ligands that counteract inhibition of the nicotinic acetylcholine receptor by cocaine and MK-801

Synthesis and Pharmacology of Site Specific Cocaine Abuse Treatment Agents: 8-Substituted Isotropane (3-Azabicyclo[3.2.1]octane) Dopamine Uptake Inhibitors

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